We propose a copula-based joint modeling framework for mixed longitudinal responses. Our approach permits all model parameters to vary with time, and thus will enable researchers to reveal dynamic response-predictor relationships and response-response associations. We call the new class of models TIMECOP because we model dependence using a time-varying copula. We develop a one-step estimation procedure for the TIMECOP parameter vector, and also describe how to estimate standard errors. We investigate the finite sample performance of our procedure via three simulation studies, one of which shows that our procedure performs well under ignorable missingness. We also illustrate the applicability of our approach by analyzing binary and continuous responses from the Women's Interagency HIV Study and a smoking cessation program.

INTRODUCTION: Differences in the rate of nicotine metabolism between genders and different races have been hypothesized to contribute to disparities in smoking rate, susceptibility to addiction, and ability to quit smoking. The purpose of this study was to determine the effect of race and gender on the rate of nicotine metabolism as indicated by the nicotine metabolite ratio (NMR) in adolescent smokers. METHODS: One hundred and fifty-nine adolescent smokers aged 13-17 were given 2mg of deuterium-labeled cotinine (cotinine-d4). The NMR was calculated as the ratio of concentrations of deuterium-labeled 3-hydroxycotinine (ng/ml) to cotinine-d4 (ng/ml) in saliva and is a validated biomarker of the rate of nicotine metabolism. RESULTS: The sample was 67.3% female and racially mixed. On average, Whites had the fastest rates of metabolism compared with both Blacks/African Americans (p < .01) and Asians (p = .01). The NMR was similar between males and females (p = .70). Among the 19 girls who reported using estrogen-containing contraceptives, there was no significant difference in NMR compared with the 83 girls who did not use contraceptives (p = .24) or the 10 who used progestin-only contraceptives (p = .45). CONCLUSIONS: Among adolescent smokers, racial variations in rates of nicotine metabolism were similar to those that have been reported in adult smokers. In contrast to findings in adult smokers, the NMR did not vary significantly by gender or self-reported hormone use.

Introduction

Intermittent smoking is common among adolescent smokers, but little is known about adolescent intermittent smokers (ITS). This study describes a cohort of adolescent ITS and compares them to adolescent daily smokers (DS) for the purpose of providing a more detailed characterization of adolescent ITS, specifically patterns of smoking, level of self-reported addiction, and experience with cessation

Methods

Participants were 124 ITS and 55 DS. ITS were defined as smoking at least monthly but <30 days per month; and DS as smoking daily. Participants completed demographic, smoking and addiction surveys including the HONC and mFTQ.

Results

ITS started smoking at an older age, smoked fewer cigarettes per day and scored significantly lower on addiction scales, but had similar difficulty to DS in quitting smoking with similar numbers of reported quit attempts. These differences remained after adjusting for years of smoking. ITS were more likely to smoke in social situations, while DS were more likely to smoke when angry. Both groups were equally likely to report smoking when drinking alcohol.

Conclusions

We documented significant differences in smoking related behaviors between adolescent ITS and DS. Importantly, we also found that, despite low level infrequent smoking, ITS reported difficulty in quitting smoking. Given the risks from light and intermittent smoking, it is essential that we develop a greater understanding of adolescent ITS, including their difficulty in quitting and the contextual factors influencing their smoking, so that we may develop new targeted interventions.

Background

Nondaily or intermittent smokers (ITS) are increasingly common, but how much nicotine, if any, ITS take in and how quickly they metabolize it has not yet been studied.

Methods

We compared carbon monoxide (CO), urinary cotinine, and nicotine metabolism [nicotine metabolite ratio (NMR): 3-hydroxycotinine:cotinine] in 224 ITS and 222 daily smokers (DS). Effects of gender and ethnicity were examined.

Results

DS had higher cotinine concentrations than ITS (1,396 ± 69 vs. 478 ± 44 ng/mL), attributable to higher cigarettes per day (CPD). In both groups, cotinine rose more slowly as CPD increased. There were no differences in cotinine between White (WH) and African American (AA) DS; among ITS, AA cotinine was over twice that of WH. Among DS, CO was significantly higher among WH than AA smokers, but significantly lower among WH ITS than AA ITS. Although AA ITS smoked more than WH ITS (CPD: 4.13 ± 0.55 vs. 3.31 ± 0.41), this did not account for the observed cotinine nor CO differences. There were no differences in NMR by group or race, nor any gender effects.

Conclusions

At comparable CPD, DS' and ITS' intake of nicotine per cigarette was similar, as were their rates of nicotine metabolism. Among ITS, AA smokers smoke more and take in more nicotine per cigarette than WH ITS, consistent with the view of ITS as a heterogeneous group.

Impact

Differences in nicotine intake per cigarette and metabolism likely cannot account for differences in DS and ITS smoking. Future studies should explore ethnic differences in ITS smoking.

Introduction

Differences in the rate of nicotine metabolism between genders and different races have been hypothesized to contribute to disparities in smoking rate, susceptibility to addiction, and ability to quit smoking. The purpose of this study was to determine the effect of race and gender on the rate of nicotine metabolism as indicated by the nicotine metabolite ratio (NMR) in adolescent smokers.

Methods

One hundred and fifty-nine adolescent smokers aged 13-17 were given 2mg of deuterium-labeled cotinine (cotinine-d4). The NMR was calculated as the ratio of concentrations of deuterium-labeled 3'-hydroxycotinine (ng/ml) to cotinine-d4 (ng/ml) in saliva and is a validated biomarker of the rate of nicotine metabolism.

Results

The sample was 67.3% female and racially mixed. On average, Whites had the fastest rates of metabolism compared with both Blacks/African Americans (p < .01) and Asians (p = .01). The NMR was similar between males and females (p = .70). Among the 19 girls who reported using estrogen-containing contraceptives, there was no significant difference in NMR compared with the 83 girls who did not use contraceptives (p = .24) or the 10 who used progestin-only contraceptives (p = .45).

Conclusions

Among adolescent smokers, racial variations in rates of nicotine metabolism were similar to those that have been reported in adult smokers. In contrast to findings in adult smokers, the NMR did not vary significantly by gender or self-reported hormone use.

Motivated by an empirical analysis of ecological momentary assessment data (EMA) collected in a smoking cessation study, we propose a joint modeling technique for estimating the time-varying association between two intensively measured longitudinal responses: a continuous one and a binary one. A major challenge in joint modeling these responses is the lack of a multivariate distribution. We suggest introducing a normal latent variable underlying the binary response and factorizing the model into two components: a marginal model for the continuous response, and a conditional model for the binary response given the continuous response. We develop a two-stage estimation procedure and establish the asymptotic normality of the resulting estimators. We also derived the standard error formulas for estimated coefficients. We conduct a Monte Carlo simulation study to assess the finite sample performance of our procedure. The proposed method is illustrated by an empirical analysis of smoking cessation data, in which the question of interest is to investigate the association between urge to smoke, continuous response, and the status of alcohol use, the binary response, and how this association varies over time.

Aims

The purpose of this study was to determine the association between the nicotine metabolic rate and smoking behavior, including addiction, in adolescent smokers.

Design

Baseline data from a prospective study of adolescent smoking behaviors and nicotine metabolism.

Setting

The setting was an out-patient university hospital in San Francisco.

Participants

Adolescent smokers (n = 164) aged 13-17 years old.

Measurements

Participants completed self-report measures of smoking behavior and nicotine dependence (modified Fagerström Tolerance Questionnaire: mFTQ). The nicotine metabolite ratio (NMR), a phenotypic marker of the rate of nicotine metabolism, was calculated using the ratio of concentrations of deuterium-labeled 3'-hydroxycotinine to cotinine-d(4) .

Findings

Participants reported smoking a mean of 2.86 cigarettes per day (CPD) [median = 1.78, standard deviation (SD) = 3.35] for 1.37 years (median = 1.0, SD = 1.36). Results from multivariate analyses accounting for age, race/ethnicity, gender and duration of smoking indicated that slower metabolizers smoked more CPD than faster metabolizers (the NMR was inversely related to CPD; P = 0.02). Slower metabolizers also showed greater dependence on the mFTQ (NMR was negatively associated with the mFTQ; P = 0.02).

Conclusions

In adolescence, slower clearance of nicotine may be associated with greater levels of addiction, perhaps mediated by a greater number of cigarettes smoked.

AIMS: The purpose of this study was to determine the association between the nicotine metabolic rate and smoking behavior, including addiction, in adolescent smokers. DESIGN: Baseline data from a prospective study of adolescent smoking behaviors and nicotine metabolism. SETTING: The setting was an out-patient university hospital in San Francisco. PARTICIPANTS: Adolescent smokers (n = 164) aged 13-17 years old. MEASUREMENTS: Participants completed self-report measures of smoking behavior and nicotine dependence (modified Fagerström Tolerance Questionnaire: mFTQ). The nicotine metabolite ratio (NMR), a phenotypic marker of the rate of nicotine metabolism, was calculated using the ratio of concentrations of deuterium-labeled 3-hydroxycotinine to cotinine-d(4) . FINDINGS: Participants reported smoking a mean of 2.86 cigarettes per day (CPD) [median = 1.78, standard deviation (SD) = 3.35] for 1.37 years (median = 1.0, SD = 1.36). Results from multivariate analyses accounting for age, race/ethnicity, gender and duration of smoking indicated that slower metabolizers smoked more CPD than faster metabolizers (the NMR was inversely related to CPD; P = 0.02). Slower metabolizers also showed greater dependence on the mFTQ (NMR was negatively associated with the mFTQ; P = 0.02). CONCLUSIONS: In adolescence, slower clearance of nicotine may be associated with greater levels of addiction, perhaps mediated by a greater number of cigarettes smoked.